Polymorph form II of tanaproget

ABSTRACT

Tanaproget polymorph Form II, processes for preparing tanaproget polymorph Form II, pharmaceutical compositions including tanaproget polymorph Form II, micronized tanaproget polymorph Form II, and processes for converting Form II to tanaproget Form I are provided. Also provided are methods of contraception, hormone replacement therapy, stimulation of food intake and treating or preventing uterine myometrial fibroids, benign prostatic hypertrophy, benign and malignant neoplastic disease, dysfunctional bleeding, uterine leiomyomata, endometriosis, polycystic ovary syndrome, or carcinomas and adenocarcinomas comprising administering polymorph Form II to a mammalian subject.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.12/792,978, filed Jun. 3, 2010, now U.S. Pat. No. 7,968,709, issued Jun.28, 2011, which is a divisional of U.S. patent application Ser. No.11/412,015, filed Apr. 26, 2006, now U.S. Pat. No. 7,759,341, issuedJul. 20, 2010, which claims the benefit of the priority of U.S.Provisional Patent Application No. 60/675,737, filed Apr. 28, 2005, nowexpired. These priority applications are herein incorporated byreference.

BACKGROUND OF THE INVENTION

A novel tanaproget polymorph Form II and compositions containing thesame are provided as described herein.

Intracellular receptors (IR) form a class of structurally related generegulators known as “ligand dependent transcription factors”. Thesteroid receptor family is a subset of the IR family, includingprogesterone receptor (PR), estrogen receptor (ER), androgen receptor(AR), glucocorticoid receptor (GR), and mineralocorticoid receptor (MR).

The natural hormone, or ligand, for the PR is the steroid progesterone,but synthetic compounds, such as medroxyprogesterone acetate orlevonorgestrel, have been made which also serve as ligands. Once aligand is present in the fluid surrounding a cell, it passes through themembrane via passive diffusion, and binds to the IR to create areceptor/ligand complex. This complex binds to specific gene promoterspresent in the cell's DNA. Once bound to the DNA the complex modulatesthe production of mRNA and protein encoded by that gene.

A compound that binds to an IR and mimics the action of the naturalhormone is termed an agonist, whilst a compound which inhibits theeffect of the hormone is an antagonist.

PR agonists (natural and synthetic) are known to play an important rolein the health of women. PR agonists are used in birth controlcompositions, typically in the presence of an ER agonist, alternativelythey may be used in conjunction with a PR antagonist. ER agonists areused to treat the symptoms of menopause, but have been associated with aproliferative effect on the uterus which can lead to an increased riskof uterine cancers. Co-administration of a PR agonist reduces/ablatesthat risk.

Tanaproget,5-(4,4-dimethyl-2-thioxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrile,is a progesterone receptor modulator and is effective in contraception,hormone replacement therapy, and treating carcinomas andadenocarcinomas, dysfunctional bleeding, uterine leiomyomata,endometriosis, and polycystic ovary syndrome.

What is needed in the art are alternate forms of tanaproget.

SUMMARY OF THE INVENTION

In one aspect, tanaproget polymorph Form II is provided.

In a further aspect, micronized tanaproget polymorph Form II isprovided.

In another aspect, a process for preparing tanaproget polymorph Form IIis provided.

In still a further aspect, a pharmaceutical composition containingtanaproget polymorph Form II is provided.

In yet another aspect, a kit containing tanaproget polymorph Form II isprovided.

In a further aspect, a method of preparing a pharmaceutical compositioncontaining tanaproget polymorph Form II is provided.

In yet another aspect, a process for preparing tanaproget polymorph FormI from tanaproget polymorph Form II is provided.

In a further aspect, methods of contraception, hormone replacementtherapy, and stimulation of food intake using tanaproget polymorph FormII are provided.

In still another aspect, methods of treating and preventing uterinemyometrial fibroids, benign prostatic hypertrophy, benign and malignantneoplastic disease, dysfunctional bleeding, uterine leiomyomata,endometriosis, polycystic ovary syndrome, and carcinomas andadenocarcinomas of the pituitary, endometrium, kidney, ovary, breast,colon, and prostate and other hormone-dependent tumors using tanaprogetpolymorph Form II are provided.

Other aspects and advantages of the present invention are describedfurther in the following detailed description of the preferredembodiments thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 provides the X-ray diffraction pattern for tanaproget polymorphForm II.

FIG. 2 provides the differential scanning calorimetry thermogram fortanaproget polymorph Form II.

DETAILED DESCRIPTION OF THE INVENTION

A novel polymorph of tanaproget, denoted herein as Form II, isdescribed. Form II differs from Form I in the structure of the crystallattice of tanaproget Form I and in its chemical properties.

As used herein, “tanaproget” or “Form I” refers to tanaproget, i.e.,5-(4,4-dimethyl-2-thioxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1-methyl-1H-pyrrole-2-carbonitrile,regardless of particle size or purity. Tanaproget can be purifiedaccording to the procedure set forth in US Patent ApplicationPublication No. US 2005-0272702 A1, which is hereby incorporated byreference.

In another embodiment, tanaproget Form I is purified byrecrystallization. Desirably, the tanaproget is recrystallized fromacetone and water. More desirably, the tanaproget is dissolved inacetone, the acetone solution heated, water added to the heated acetonesolution, and the acetone/water solution cooled to provide purifiedtanaproget. This purification specifically includes dissolving crudetanaproget in acetone and heating the solution to about 45 to about 51°C. After circulating the heated solution through a carbon filter for atleast about 4 hours, the filtered solution was concentrated usingprocedures known to those of skill in the art. After adding water to theconcentrated solution, desirably at a rate which does not cool therefluxing acetone solution, the acetone/water solution is cooled toabout −6 to about 0° C. Desirably, the acetone/water solution is cooledat a rate of less than about 0.5° C./minute. After holding the batch atthe reduced temperature for at least about 3 hours, the precipitated,purified tanaproget is collected using filtration. The collected solidis washed with a water/acetone mixture, desirably washing the solidtwice with a 1:1 water/acetone mixture. The washed purified tanaprogetis then dried at less than 35° C. for about 4 hours. Further drying atless than about 50° C. is performed to remove residual acetone/water asmeasured by spectroscopic methods.

“Tanaproget” or “Form I” also refers to both non-micronized andmicronized forms of the same. Micronization of tanaproget is typicallyaccomplished under nitrogen and conventional micronizing techniques, forexample with a Trost or jet mill, applied to non-micronized tanaproget.One method of preparation of non-micronized tanaproget is described inU.S. Pat. No. 6,436,929 and another is generally described in US PatentApplication Publication No. US-2005-0272702-A1, which are herebyincorporated by reference. Desirably, the non-micronized tanaproget isprepared as described in US Patent Application Publication No.US-2005-0272702-A1. However, the novel polymorph Form II is not limitedto the method by which the non-micronized tanaproget is produced.

Micronized tanaproget prepared or used typically has a particle size ofless than about 20 μm, and desirably less than about 15 μm. Desirably,90% of the particles are less than or equal to about 20 μm and 50% areless than or equal to about 15 μm, and more desirably less than about 10μm, as determined by the Malvern method, which is readily understood byone of skill in the art. More desirably, most of the particles are lessthan or equal to about 10 μm.

A. Spectroscopic Identification of Form II

Tanaproget Form I has a differential scanning calorimetry thermogramwhich includes an endotherm peak of about 230° C. Further, the X-raydiffraction (XRD) pattern contains peaks at 2θ of about 6.6°, 10.3°,14.4°, 19.8°, 23.8°, 26.3°, and 29.1°.

The XRD pattern of tanaproget polymorph Form II differs from the XRDpattern of Form I and includes peaks at 2θ of about 6.0°, 8.3°, 12.0°,21.4°, and 23.4°. See, FIG. 1. The differential scanning calorimetry(DSC) thermogram of Form II also differs from the DSC thermogram of FormI and has a T_(onset) of about 219° C. See, FIG. 2.

B. Preparing the Form II Tanaproget Polymorph

The Form II tanaproget polymorph is typically prepared byrecrystallizing non-micronized or micronized tanaproget Form I fromselected solvent systems. Preferred solvent systems for use in preparingForm II include, without limitation, the methylene chloride and pentanesolvent system; the acetonitrile and water solvent system; and themethanol and water solvent system.

(i) The Methylene Chloride/Pentane Solvent System

In one embodiment, Form II is prepared using the methylenechloride/pentane solvent system. In this process, Form I is dissolved inmethylene chloride and optionally warmed to temperatures of about refluxtemperatures. The methylene chloride solution is then optionallyconcentrated and pentane is added. The pentane can be layered onto themethylene chloride solution and mixed therein or mixed directly into themethylene chloride solution. The methylene chloride/pentane solution isthereby cooled, desirably to about 20° C. By doing so, tanaprogetpolymorph Form II precipitates from the methylene chloride/pentanesolution and is collected using techniques known in the art. Thecollected Form II can then be dried using techniques known in the artand include the use of reduced pressures and elevated temperatures,among other techniques.

(ii) The Acetonitrile/Water Solvent System

In another embodiment, Form II is prepared using the acetonitrile/watersolvent system. In this process, Form I is dissolved in acetonitrile,optionally warmed to temperatures of about reflux temperatures. Theacetonitrile solution is then optionally concentrated and water isadded. The water can be layered onto the acetonitrile solution and mixedtherein or mixed directly into the acetonitrile solution. Theacetonitrile/water solution is thereby cooled, desirably to roomtemperature or below. By doing so, tanaproget polymorph Form IIprecipitates from the acetonitrile/water solution and is collected usingtechniques known in the art. The collected Form II can then be driedusing techniques known in the art and include the use of reducedpressures and elevated temperatures, among other techniques.

(iii) The Methanol/Water Solvent System

In a further embodiment, Form II is prepared using the methanol/watersolvent system. In this process, Form I is dissolved in methanol,optionally warmed to temperatures of about reflux temperatures. Themethanol solution is then optionally concentrated and water is added.The water can be layered onto the methanol solution and mixed therein ormixed directly into the methanol solution. The methanol/water solutionis thereby cooled, desirably to room temperature or below. By doing so,tanaproget polymorph Form II precipitates from the methanol/watersolution and is collected using techniques known in the art. Thecollected Form II can then be dried using techniques known in the artand include the use of reduced pressures and elevated temperatures,among other techniques.

C. Micronized Tanaproget Form II

Tanaproget Form II can be micronized under nitrogen and conventionalmicronizing techniques, for example with a Trost or jet mill, asdiscussed above for micronized tanaproget Form I.

Micronized tanaproget Form II typically has a median particle size ofless than about 20 μm, desirably less than about 15 μm, and moredesirably less than about 10 μm. Specifically, 90% of the particles areless than or equal to about 20 μm and 50% are less than or equal toabout 15 μm as determined by the Malvern method, which is readilyunderstood by one of skill in the art.

In one embodiment, micronized5-(4,4-dimethyl-2-thioxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1-methyl-1H-pyrrole-2-carbonitrileForm II having a particle size less than about 20 μm is provided.

D. Compositions Containing the Form II Tanaproget Polymorph

Also provided are compositions, desirably pharmaceutical compositions,containing tanaproget polymorph Form II alone or in combination withForm I. The compositions typically contain a pharmaceutically acceptablecarrier, but can also contain other suitable components. Typically, theadditional components are inert and do not interfere with the functionof the required components of the compositions. The compositions canthereby further include other adjuvants, syrups, elixirs, diluents,binders, lubricants, surfactants, granulating agents, disintegratingagents, emollients, metal chelators, pH adjustors, surfactants, fillers,disintegrants, and combinations thereof, among others.

Adjuvants can include, without limitation, flavoring agents, coloringagents, preservatives, and supplemental antioxidants, which can includevitamin E, ascorbic acid, butylated hydroxytoluene (BHT) and butylatedhydroxyanisole (BHA).

Binders can include, without limitation, povidone, cellulose,methylcellulose, hydroxymethylcellulose, carboxymethylcellulose calcium,carboxymethylcellulose sodium, hydroxypropylcellulose,hydroxypropylmethylcellulose phthalate, noncrystalline cellulose,polypropylpyrrolidone, polyvinylpyrrolidone (povidone, PVP), gelatin,gum arabic and acacia, polyethylene glycols, starch, sugars such assucrose, kaolin, dextrose, and lactose, cholesterol, tragacanth, stearicacid, gelatin, casein, lecithin (phosphatides), cetostearyl alcohol,cetyl alcohol, cetyl esters wax, dextrates, dextrin, glycerylmonooleate, glyceryl monostearate, glyceryl palmitostearate,polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives,polyoxyethylene stearates, polyvinyl alcohol, and gelatin, among others.In one embodiment, the binder is povidone.

Lubricants can include light anhydrous silicic acid, talc, stearic acid,sodium lauryl sulfate, magnesium stearate and sodium stearyl furamate,among others. In one embodiment, the lubricant is magnesium stearate.

Granulating agents can include, without limitation, silicon dioxide,starch, calcium carbonate, pectin, crospovidone, and polyplasdone, amongothers.

Disintegrating agents or disintegrants can include starch,carboxymethylcellulose, substituted hydroxypropylcellulose, sodiumbicarbonate, calcium phosphate, calcium citrate, sodium starchglycolate, pregelatinized starch or crospovidone, among others.

Emollients can include, without limitation, stearyl alcohol, mink oil,cetyl alcohol, oleyl alcohol, isopropyl laurate, polyethylene glycol,olive oil, petroleum jelly, palmitic acid, oleic acid, and myristylmyristate.

Surfactants can include polysorbates, sorbitan esters, poloxamer, orsodium lauryl sulfate. In one embodiment, the surfactant is sodiumlauryl sulfate.

Metal chelators can include physiologically acceptable chelating agentsincluding edetic acid, malic acid, or fumaric acid. In one embodiment,the metal chelator is edetic acid.

pH adjusters can also be utilized to adjust the pH of a solutioncontaining tanaproget to about 4 to about 6. In one embodiment, the pHof a solution containing tanaproget is adjusted to a pH of about 4.6. pHadjustors can include physiologically acceptable agents including citricacid, ascorbic acid, fumaric acid, or malic acid, and salts thereof. Inone embodiment, the pH adjuster is citric acid.

Additional fillers that can be used in the composition include mannitol,calcium phosphate, pregelatinized starch, or sucrose.

E. Methods of Using the Form II Tanaproget Polymorph

Further provided are methods of delivering tanaproget polymorph Form IIto a patient, where the method includes administering Form II.

The dosage requirements of Form II may vary based on the severity of thesymptoms presented and the particular subject being treated. Treatmentcan be initiated with small dosages less than the optimum dose of FormII. Thereafter the dosage is increased until the optimum effect underthe circumstances is reached. Precise dosages will be determined by theadministering physician based on experience with the individual subjecttreated. In general, Form II is most desirably administered at aconcentration that will generally afford effective results withoutcausing any unacceptable harmful or deleterious side effects. Forexample, an effective amount of Form II is generally, e.g., about 0.05mg to about 1 mg, about 0.05 mg to about 0.3 mg, about 0.05 mg, about0.075 mg, about 0.1 mg, about 0.15 mg, about 0.2 mg, or about 0.3 mg.

Form II is therefore useful in contraception and hormone replacementtherapy. Form II is also useful in contraception and the treatmentand/or prevention of uterine myometrial fibroids, benign prostatichypertrophy, benign and malignant neoplastic disease, dysfunctionalbleeding, uterine leiomyomata, endometriosis, polycystic ovary syndrome,and carcinomas and adenocarcinomas of the pituitary, endometrium,kidney, ovary, breast, colon, and prostate and other hormone-dependenttumors. Additional uses of Form II include stimulation of food intake.

Tanaproget polymorph Form II can be formulated in any form suitable forthe desired route of delivery using a pharmaceutically effective amountof Form II. For example, Form II can be delivered by a route such asoral, dermal, transdermal, intrabronchial, intranasal, intravenous,intramuscular, subcutaneous, parenteral, intraperitoneal, intranasal,vaginal, rectal, sublingual, intracranial, epidural, intratracheal, orby sustained release. Desirably, delivery is oral.

For example, Form II may be formulated for administration orally in suchforms as tablets, capsules, microcapsules, dispersible powders,granules, or suspensions containing, for example, from about 0.05 to 5%of suspending agent, syrups containing, for example, from about 10 to50% of sugar, and elixirs containing, for example, from about 20 to 50%ethanol, and the like. The preferred pharmaceutical compositions fromthe standpoint of ease of preparation and administration are solidcompositions, particularly tablets and hard-filled or liquid-filledcapsules.

Form II may also be administered parenterally or intraperitoneally.Solutions or suspensions of Form II can be prepared in water suitablymixed with a surfactant such as hydroxypropylcellulose. Dispersions canalso be prepared in glycerol, liquid, polyethylene glycols and mixturesthereof in oils. Under ordinary conditions of storage and use, thesepreparations contain a preservative to prevent the growth ofmicroorganisms. Typically, such sterile injectable solutions orsuspensions contain from about 0.05 to 5% suspending agent in anisotonic medium. Such pharmaceutical preparations may contain, forexample, from about 25 to about 90% of the active ingredient incombination with the carrier, more usually between about 5% and 60% byweight.

In another embodiment, Form II is delivered intravenously,intramuscularly, subcutaneously, parenterally and intraperitoneally inthe form of sterile injectable solutions, suspensions, dispersions, andpowders which are fluid to the extent that easy syringe ability exits.Such injectable compositions are sterile, stable under conditions ofmanufacture and storage, and free of the contaminating action ofmicroorganisms such as bacteria and fungi.

The carrier can be a solvent or dispersion medium containing, forexample, water, ethanol (e.g., glycerol, propylene glycol and liquidpolyethylene glycol), oils, and mixtures thereof. Desirably the liquidcarrier is water. In one embodiment, the oil is vegetable oil.Optionally, the liquid carrier contains a suspending agent. In anotherembodiment, the liquid carrier is an isotonic medium and contains 0.05to about 5% suspending agent.

In a further embodiment, Form II is delivered rectally in the form of aconventional suppository.

In another embodiment, Form II is delivered vaginally in the form of aconventional suppository, cream, gel, ring, or coated intrauterinedevice (IUD).

In yet another embodiment, Form II is delivered intranasally orintrabronchially in the form of an aerosol.

In a further embodiment, Form II is delivered transdermally or bysustained release through the use of a transdermal patch containing FormII and an optional carrier that is inert to Form II, is nontoxic to theskin, and allows for delivery of Form II for systemic absorption intothe blood stream. Such a carrier can be a cream, ointment, paste, gel,or occlusive device. The creams and ointments can be viscous liquid orsemisolid emulsions. Pastes include absorptive powders dispersed inpetroleum or hydrophilic petroleum. Further, a variety of occlusivedevices can be utilized to release Form II into the blood stream andinclude semi-permeable membranes covering a reservoir contain the activereagents, or a matrix containing the reactive reagents.

The use of sustained delivery devices can be desirable, in order toavoid the necessity for the patient to take medications on a dailybasis. The term “sustained delivery” is used herein to refer to delayingthe release of an active agent, i.e., tanaproget polymorph Form II,until after placement in a delivery environment, followed by a sustainedrelease of the agent at a later time. A number of sustained deliverydevices are known in the art and include hydrogels (U.S. Pat. Nos.5,266,325; 4,959,217; 5,292,515), osmotic pumps (U.S. Pat. Nos.4,295,987 and 5,273,752 and European Patent No. 314,206, among others);hydrophobic membrane materials, such as ethylenemethacrylate (EMA) andethylenevinylacetate (EVA); bioresorbable polymer systems (InternationalPatent Publication No. WO 98/44964 and U.S. Pat. Nos. 5,756,127 and5,854,388); and other bioresorbable implant devices composed of, forexample, polyesters, polyanhydrides, or lactic acid/glycolic acidcopolymers (U.S. Pat. No. 5,817,343). For use in such sustained deliverydevices, Form II can be formulated as described herein. See, U.S. Pat.Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719.

Desirably, Form II is formed into a suitable dosing unit for delivery toa patient. Suitable dosing units include oral dosing units, such as adirectly compressible tablets, capsules, powders, suspensions,microcapsules, dispersible powders, granules, suspensions, syrups,elixirs, and aerosols. Desirably, Form II is compressed into a tablet,which is optionally added to a capsule, or Form II is added directly toa capsule. Form II can also be formulated for delivery by other suitableroutes. These dosing units are readily prepared using the methodsdescribed herein and those known to those of skill in the art.

Solid forms, including tablets, caplets, and capsules containingtanaproget Form II can be formed by dry blending tanaproget with thecomponents described above. In one embodiment, the capsules utilizedinclude hydroxypropyl methylcellulose, hypromellose capsule, or a hardshell gelatin capsule. The tablets or caplets that contain tanaprogetare optionally film-coated. Suitable film-coatings are known to those ofskill in the art. For example, the film-coating can be selected fromamong polymers such as hydroxypropylmethylcellulose, ethyl cellulose,polyvinyl alcohol, and combinations thereof.

A pharmaceutically effective amount of Form II can vary depending on theother components of the composition being delivered, mode of delivery,severity of the condition being treated, the patient's agent and weight,and any other active ingredients used in the composition. The dosingregimen can also be adjusted to provide the optimal therapeuticresponse. Several divided doses can be delivered daily, e.g., in divideddoses 2 to 4 times a day, or a single dose can be delivered. The dosecan however be proportionally reduced or increased as indicated by theexigencies of the therapeutic situation. In one embodiment, the deliveryis on a daily, weekly, or monthly basis. In another embodiment, thedelivery is on a daily delivery. However, daily dosages can be loweredor raised based on the periodic delivery.

It is contemplated that when Form II is used for contraception orhormone replacement therapy, it can be administered in conjunction withone or more other progesterone receptor agonists, estrogen receptoragonists, progesterone receptor antagonists, and selective estrogenreceptor modulators, among others.

When utilized for treating neoplastic disease, carcinomas, andadenocarcinomas, Form II can be administered in conjunction with one ormore chemotherapeutic agents which can readily be selected by one ofskill in the art.

F. Kits Containing Tanaproget Polymorph Form II

Also provided are kits or packages containing tanaproget polymorph FormII. Kits can include Form II or in combination with Form I and a carriersuitable for administration to a mammalian subject as discussed above.Typically, the tablets or capsules are packaged in blister packs, anddesirably Ultrx™ 2000 blister packs

The kits or packages containing Form II are designed for use in theregimens described herein. These kits are desirably designed for dailyoral delivery over 21-day, 28-day, 30-day, or 31-day cycles, amongothers, and more desirably for one oral delivery per day. When Form IIis to be delivered continuously, a package or kit can include Form II ineach tablet. When Form II is to be delivered with periodicdiscontinuation, a package or kit can include placebos on those dayswhen Form II is not delivered.

Additional components may be co-administered with Form II and includeprogestational agents, estrogens, and selective estrogen receptormodulators.

The kits are also desirably organized to indicate a single oralformulation or combination of oral formulations to be taken on each dayof the cycle, desirably including oral tablets to be taken on each ofthe days specified, and more desirably one oral tablet will contain eachof the combined daily dosages indicated.

In one embodiment, a kit can include a single phase of a daily dosage ofForm II over a 21-day, 28-day, 30-day, or 31-day cycle. Alternatively, akit can include a single phase of a daily dosage of Form II over thefirst 21 days of a 28-day, 30-day, or 31-day cycle. A kit can alsoinclude a single phase of a daily dosage of Form II over the first 28days of a 30-day or 31-day cycle.

In a further embodiment, a kit can include a single combined phase of adaily dosage of Form II and a progestational agent over a 21-day,28-day, 30-day, or 31-day cycle. Alternatively, a kit can include asingle combined phase of a daily dosage of Form II and a progestationalagent over the first 21 days of a 28-day, 30-day, or 31-day cycle. A kitcan also include a single combined phase of a daily dosage of Form IIand a progestational agent over the first 28 days of a 30-day or 31-daycycle.

In another embodiment, a 28-day kit can include a first phase of from 14to 28 daily dosage units of Form II; a second phase of from 1 to 11daily dosage units of a progestational agent; and, optionally, a thirdphase of an orally and pharmaceutically acceptable placebo for theremaining days of the cycle.

In yet a further embodiment, a 28-day kit can include a first phase offrom 14 to 21 daily dosage units of Form II; a second phase of from 1 to11 daily dosage units of a progestational agent; and, optionally, athird phase of an orally and pharmaceutically acceptable placebo for theremaining days of the cycle.

In another embodiment, a 28-day kit can include a first phase of from 18to 21 daily dosage units of Form II; a second phase of from 1 to 7 dailydose units of a progestational agent; and, optionally, an orally andpharmaceutically acceptable placebo for each of the remaining 0 to 9days in the 28-day cycle.

In yet a further embodiment, a 28-day kit can include a first phase of21 daily dosage units of Form II; a second phase of 3 daily dosage unitsfor days 22 to 24 of a progestational agent; and, optionally, a thirdphase of 4 daily units of an orally and pharmaceutically acceptableplacebo for each of days 25 to 28.

In another embodiment, a 28-day kit can include a first phase of from 14to 21 daily dosage units of a progestational agent equal inprogestational activity to about 35 to about 150 μg levonorgestrel, asecond phase of from 1 to 11 daily dosage units of Form II; andoptionally, a third phase of an orally and pharmaceutically acceptableplacebo for the remaining days of the cycle in which no antiprogestin,progestin or estrogen is administered.

In a further embodiment, a 28-day kit can include a first phase of from14 to 21 daily dosage units of a progestational agent equal inprogestational activity to about 35 to about 100 μg levonorgestrel; asecond phase of from 1 to 11 daily dosage units of Form II; andoptionally, a third phase of an orally and pharmaceutically acceptableplacebo for the remaining days of the cycle in which no antiprogestin,progestin or estrogen is administered.

Desirably, the daily dosage of Form II remains fixed in each particularphase in which it is delivered. It is further preferable that the dailydose units described are to be delivered in the order described, withthe first phase followed in order by the second and third phases. Tohelp facilitate compliance with each regimen, it is also preferred thatthe kits contain the placebo described for the final days of the cycle.

A number of packages or kits are known in the art for the use indispensing pharmaceutical agents for oral use. Desirably, the packagehas indicators for each day of the 28-day cycle, and more desirably is alabeled blister package, dial dispenser package, or bottle.

The kit can further contain instructions for administering Form II.

G. Process for Converting Form II Tanaproget Polymorph to Form I

Also provided are processes for preparing tanaproget Form I fromtanaproget polymorph Form II. Typically, Form II is converted to Form Ivia crystallization from a solvent system or directly from Form IIwithout the use of a solvent.

In one embodiment, Form II is converted to Form I by combining Form IIwith acetone and water, desirably a 1:1 ratio of acetone to water. FormII is mixed with the acetone/water solution for a time that issufficient to convert Form II to Form I. Typically, conversion of FormII to Form I occurs as Form II dissolves and Form I is recrystallized.The conversion can readily be monitored using XRD and DSC and,specifically, by monitoring the presence of the Form II XRD peaks andDSC endotherms. Complete conversion is noted by an absence of Form IIXRD peaks and DSC endotherms.

Form I can precipitate from the acetone/water solvent in about 1, 2, 3,4, 5, 6, or 6 days. Typically, Form I precipitates from theacetone/water solution, after about 1 week, and is collected usingtechniques known to those of skill in the art. However, conversion toForm I can be complete in less than 1 week or even less than 1 daydepending on the conditions utilized during the conversion and anyenvironmental factors present at the time of conversion.

In another embodiment, tanaproget polymorph Form II is converted totanaproget Form I without the use of a solvent. Typically, Form II isfirst heated to its melting point, typically to about 219 to about 229°C., more desirably about 219 to about 216° C. Heating can beaccomplished using a variety of techniques including, withoutlimitation, hot stage microscopy. Once the Form II has melted, theliquid sample is typically maintained at about 219° C. to about 229° C.to promote crystallization of the Form I tanaproget polymorph. Form I isthen collected using techniques known to those of skill in the art.

If crystallization to Form I does not occur between 219° C. and 229° C.within an acceptable period of time, the sample is slowly cooled below219° C. until crystallization does occur.

The following examples are provided to illustrate the invention and donot limit the scope thereof. One skilled in the art will appreciate thatalthough specific reagents and conditions are outlined in the followingexamples, modifications can be made which are meant to be encompassed bythe spirit and scope of the invention.

EXAMPLES Example 1 Preparation of Tanaproget Form II Polymorph fromTanaproget Form I Using Methylene Chloride/Pentane

Tanaproget Form I polymorph (6.8 g) was dissolved in methylene chloride(100 mL) at 29° C. After cooling the solution to 20° C., pentane (150mL) was added dropwise to the solution to give a suspension. Thesuspension was then filtered and the filter cake dried to giveTanaproget Form II polymorph (6.1 g).

Example 2 Preparation of Tanaproget Form II Polymorph from TanaprogetForm I Using Acetonitrile/Water

Tanaproget Form I polymorph (73.9 mg) was dissolved in acetonitrile (2mL) at 55° C. Water (about 1 mL) was then added dropwise to theacetonitrile solution. The suspension was maintained at room temperatureovernight and then at 4° C. for 2 days. The sample was centrifuged andcrystallized Tanaproget Form II polymorph (about 15 mg) was recoveredand air dried.

Example 3 Preparation of Tanaproget Form I Polymorph from TanaprogetForm II

Tanaproget polymorph Form II (117.5 mg) was weighed into a 4 mLscintillation vial. Water (1 mL) and acetone (1 mL) were added and theslurry stirred for 5 days at room temperature. The sample was thencentrifuged and the recovered solid was dried under vacuum for 2 days atroom temperature to give Tanaproget Polymorph Form I. XRD and DSCanalysis indicated a complete conversion to Form I.

Example 4 Preparation of Tanaproget Form II Polymorph from TanaprogetForm I Using Methanol/Water

Tanaproget Form I polymorph is dissolved in methanol. Water is thenadded dropwise to the methanol solution. The suspension is maintained atroom temperature overnight and then at reduced temperatures 4° C. for 2days. The sample is centrifuged and crystallized Tanaproget Form IIpolymorph is recovered and air dried.

Example 5 Preparation of Tanaproget Form I Polymorph from TanaprogetForm II Using Heat

A sample of the Form II tanaproget polymorph is heated to a temperatureof about 219° C. and about 229° C. heat until the entire sample ismelted. Once a liquid forms, the temperature is maintained between about219° C. and about 229° C. and crystallization to Form I tanaprogetpolymorph occurs. The sample is optionally cooled to below 219° C. tofurther crystallize the Form I tanaproget polymorph.

All publications cited in this specification are incorporated herein byreference herein. While the invention has been described with referenceto a particularly preferred embodiment, it will be appreciated thatmodifications can be made without departing from the spirit of theinvention. Such modifications are intended to fall within the scope ofthe appended claims.

We claim:
 1. A method of contraception comprising administeringpolymorph Form II of tanaproget having: (a) an X-ray diffraction peakpattern comprising peaks at 2θ of about 6.0°, 8.3°, 12.0°, 21.4°, and23.4°; and (b) a differential scanning calorimetry thermogram having aT_(onset) of about 219° C.; to a female of child bearing age.